1. Field of the Invention
This invention relates generally to polymers having improved biocompatibility, and more particularly, to polymers capable of releasing nitric oxide in situ when contacted with blood.
2. Description of the Related Art
Although medical devices, such as extracorporeal circuits and hemodialysis tubes, are widely used in clinical settings, the polymers typically used to fabricate such devices (PVC, polyurethane, silicone rubber, etc.) are still subject to platelet aggregation and adhesion at the polymer-blood contacting surface. Thus, patients are often given anti-clotting agents (i.e., heparin) systemically in order to reduce thrombosis on the surface of these devices. There is, therefore, a need for polymers that more closely simulate the antithrombogenic properties of the endothelial cells that line blood vessels in order to obviate the need to administer anticoagulants.
Nitric oxide (NO) is an important intracellular and intercellular messenger molecule that plays an important physiological role in platelet anti-activation, vascular relaxation, neurotransmission, and immune response. Synthetic materials that release low levels of NO would, therefore, more closely simulate the natural activity of endothelial cells, and therefore, would have improved biocompatibility.
Diazeniumdiolates are known NO release agents. Diazeniumdiolates can be prepared by the reaction of secondary amines with NO at elevated pressure as shown in Eqn. (1) on FIG. 1. In the presence of water, the diazeniumdiolate releases NO and reverts to the secondary amine as shown in Eqn. (2) on FIG. 1. Diazeniumdiolates have been incorporated into polymeric films and used to fabricate intravascular sensors with improved in vivo sensor performance and as internal coatings for tubing in extracorporeal circuits to prevent thrombus formation resulting from prolonged blood contact.
The disclosed approaches taken for preparing NO-releasing polymers include anchoring the diazeniumdiolate to the polymer matrix and anchoring the diazeniumdiolate to fumed silica, of the type already used as a filler in polymers. In one known embodiment, hydroxy-terminated polydimethylsiloxane (or silicone rubber), which is widely used for medical purposes, was crosslinked with a diaminopropyl-trimethoxy silane cross-linking agent, specifically N-(6-aminohexyl)aminopropyl-trimethoxysilane. The cross-linked silicone rubber was then soaked in a solvent, purged with an inert gas, and loaded with NO under pressure.
In another known embodiment, a diaminopropyl-trimethoxy silane was coupled with fumed silica to form diamino-silica. The diamino-silica was charged with NO under pressure to form diazeniumdiolated fumed silica. The diazeniumdiolated fumed silica was then used as a reinforcing filler in silicone rubber films.
In the aforementioned known embodiments, long term release of NO was observed (over at least 10 days), the release rate being higher during the first couple of days and decreasing thereafter. The cross-linked silicone rubber generated only 13% of the theoretical amount of NO, while the fumed silica-filled silicone rubber released only 38% of the theoretical amount.
Experiments conducted in vitro with oxygen-sensing catheters coated with diazeniumdiolate-doped silicone rubber indicate that the diazeniumdiolate and its decomposition products (N,N′-dimethylhexadiamine and the corresponding nitrosamine) have been shown to leach from the polymer films into aqueous soaking solutions. While systemic administration of diazeniumdiolates has been suggested (see, U.S. Pat. No. 5,155,137), it is not clear whether the original species and/or its corresponding decomposition products are safe for human use in this manner. There have been no published reports regarding the specific toxicity of N,N′-dimethyl-N-nitroso-1,6-hexadiamine, for example. However, it has been reported that 90% of the more than 300 nitrosamines that have been tested exhibit carcinogenic properties. Therefore, there is a need for a NO-releasing polymer that does not permit, or at least minimizes, leaching of the diazeniumdiolate and/or its decomposition products, and particularly nitrosamines, into the blood.
Prior art methods of minimizing leaching have included the use of more hydrophobic polymers; the use of linear polyethylenimines rather than branched diamines to form the diazeniumdiolate; the addition of a top coat of un-doped polymer over the diazeniumdiolate donor molecule-doped polymer; and covalent attachment of the diazeniumdiolate group to the polymer backbone. However, leaching can still occur through the polymers having a hydrophilic nature. And, for more hydrophobic embodiments, such as silicone rubber cross-linked with a diazeniumdiolate, other toxic species are generated and released in addition to NO. While anchoring the diazeniumdiolate to silica particles helps control leaching of the diazeniumdiolate and its decomposition products from the polymer, the silica particles are subject to leaching. There is, therefore, a need for polymers having NO-releasing capabilities that do not leach undesired, and potentially toxic, matter into the surrounding aqueous environment.